US 7737147 B2
Methods for treatment of sexual dysfunction in men and women using combinations of phosphodiesterase (PDE) type 5 inhibitors and l-deprenyl or propargylamine compounds are described. Methods of reducing the dosage and preventing the side effects of PDE type 5 inhibitors are also described. The methods comprise administering a therapeutically effective amount of l-deprenyl or propargylamine compounds (also called monoamine oxidase [MAO] inhibitors) in combination with PDE inhibitors. Stimulation of nitric oxide production and vasodilation by l-deprenyl and propargylamine compounds augments the actions of PDE inhibitors or other drugs and methods used in the treatment of sexual dysfunction. The composition described here enhances the actions of PDE inhibitors primarily by increasing the generation of cyclic GMP by stimulating the nitric oxide pathway and secondarily by providing several additional benefits such as enhanced dopamine activity. Methods of enhancing the efficacy of various PDE inhibitors in the treatment of a number of disorders other than sexual dysfunction are also disclosed.
1. A method for treating erectile dysfunction in a human male, comprising administering to the human male in need thereof an effective amount of a pharmaceutical composition comprising:
a phosphodiesterase type 5 inhibitor and an MAO inhibitor, wherein the MAO inhibitor is a deprenyl or propargylamine compound.
2. A method of
3. A method according to
4. A method according to
5. A method according to
6. A method according to
7. A method according to
8. A method according to
9. A method according to
10. A method according to
11. A method according to
12. A method according to
13. A method according to
14. A method according to
15. A method according to
16. A method according to
17. A method according to
18. A method for treating erectile dysfunction in a human male, comprising:
administering to the human male in need thereof, an effective amount of a pharmaceutical composition comprising a phosphodiesterase type 5 inhibitor; and an MAO inhibitor selected from
deprenyl or propargylamine compounds, to enhance the effects of other modalities of treatment.
19. A method according to
This application is continuation-in-part of Ser. No. 09/881,199, filed Jul. 27, 2000, now U.S. Pat. No. 6,432,991, Ser. No. 09/927,982, filed Aug. 10, 2001, now U.S. Pat. No. 6,635,337, U.S. patent application Ser. No. 10/802,000, filed Mar. 16, 2004 and U.S. provisional application No. 60/486,121,filed Jul. 11, 2003 the entire contents of which are hereby incorporated by reference.
This invention relates to methods of treating sexual dysfunction. Methods of using combinations of phosphodiesterase inhibitors and l-deprenyl or propargylamine compounds (also known as monoamine oxidase inhibitors) in the treatment of erectile dysfunction and other diseases are also provided.
No federal, state, or other government funding was used to develop this patent.
Normal sexual function involves a complex interaction of emotional, neuronal, vascular and hormonal factors. In addition sexuality incorporates personal, family, social and religious beliefs and is altered with aging, health status, and personal experience (Tomlinson, 2004).
A disruption in any of these areas may lead to sexual dysfunction. Sexuality in females may particularly involve many brain-mediated responses. About 43 percent (40 million) women in the US experience some form of sexual dysfunction. Sexual dysfunction in a female may include hypoactive sexual desire disorders, arousal disorders, orgasmic, or sexual pain disorders. Physical and emotional stimulation lead to breast and genital vasodilation and clitoral engorgement. In the female, dilation and engorgement of the blood vessels in the labia and tissue surrounding the vagina produce an orgasmic response.
Male sexual dysfunction may include erectile dysfunction and impotence. Erectile dysfunction (ED) in the male is defined as the inability to maintain an erect penis with sufficient rigidity to allow sexual intercourse. Erectile dysfunction is a common problem affecting about 30 million men in the US (NIH, 1993). It is estimated that the world-wide incidence of ED will increase from 152 million in 1995 to 322 million men by the year 2025 (Ayta et al; 1999).
It is an age-related condition with about 39% of men over 40 and 67% of men over 70 years suffering from erectile dysfunction (Seftel, 2003). Many conditions such as atherosclerosis can reduce blood flow to the penis, causing ED. Other conditions such as diabetes, hypertension, hyperlipidemia, and cigarette smoking also will lead to ED. Normal erection is mediated through the central nervous system which transmits psychogenic and sensory stimuli to the sympathetic nervous system which controls penile blood flow (Steif, 2003). The arterial blood vessels dilate and deliver blood to the penis, which enables the corpora cavernosa sinus system to become engorged with blood. Vasodilation of the cavernosal arteries and closure of the venous drainage in the penis produce an erection. The hypothalimic-pituitary-testicular axis also has a role as testosterone is required for normal libido (Rhoden, 2002).
Any psychological, neurologic, vascular, urogenital and endocrine abnormality may cause erectile dysfunction. Diabetes is one of the most common causes of ED (DeAngelis, 2001; Utkan, 2001). Other factors leading to ED are smoking, vascular disease, atherosclerosis, hypertension (Burchardt, 2000), hypercholesterolemia, renal failure, injury, surgery, hypogonadism and drugs. A variety of drugs can initiate and accelerate erectile dysfunction (Galle, 2003). These drugs include antihypertensives like beta adrenoreceptor blockers, diuretics, digoxin, antidepressants and antipsychotics, histamine-2 receptor antagonists, alcohol, opiates, amphetamines, and cocaine.
About 80% of patients with ED develop the condition because of a drug or some organic illness. The remaining 20% have a primary psychogenic cause (Rosen, 2001). Psychogenic ED may be treated with behavioral therapy (DeBeradis, 2003), which is successful in half of the patients. If ED is due to organic illness, or if it is psychogenic, but cannot be corrected by behavioral therapy, drug therapy is used (Galle, 2003; Carson 2000).
Current Methods for Treatment of ED
Phosphodiesterase (PDE) inhibitors are a class of intracelleular enzymes which mediate the catabolism of second messengers like cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). These enzymes have been classified into at least eleven groups (types I-XI) and various subclasses based on their amino acid sequence and substrate specificity (Polson, 1996; Trophy, 2000). The various PDE differ in their tissue, cellular distribution, and their specificity towards cAMP or cGMP. (table 1). So phosphodiesterase inhibitors have applications in a number of disorders including vascular, neuronal and inflammatory disorders (Zang 2002, Martin 2002, Grootendorst 2002, Burnouf, 2002). PDE inhibitors are drug candidates for the treatment of a number of disorders including heart failure, depression, asthma, inflammation, sexual dysfunction, and erectile dysfunction. Phoshodiesterase 4D has been shown to have a role in ischemic stroke (Gretarsdottir, 2003).
Nitric oxide (NO) formed from L-arginine by the enzyme nitric oxide synthase (NOS) is the prime mediator of endothelium-dependent smooth muscle relaxation and penile erection (Burnett, 1992). NO regulates vascular tone and promotes blood vessel relaxation and also has other roles in immune system, nervous system, and inflammation. NO is synthesized and released by neuronal (nNOS) and endothelial (eNOS). Both eNOS and nNOS are constitutively expressed in the endothelium and penile nerve endings (Hedlund, 2000; Bloch, 1998). Upon sexual stimulation NO is released from nerve endings, or from endothelial cells stimulated by acetylcholine from cholinergic nerve endings (Lue, 2000). It is likely that penile erection is mediated by both nNOS and eNOS. Reduced androgen levels, found in elderly men cause impaired expression of penile NO synthesis. NO synthesis is also impaired by hypertension, high levels of oxidized LDL, TNF alpha, and cAMP. NO activates a soluble guanyl cyclase that forms cyclic guanosine mononphosphate (cGMP). Cyclic GMP is the primary second messenger that mediates penile erection. Phosphodiesterase 5 inhibitors like sildenafil prevents the degradation of cGMP and enhances erectile function. NO activates prostaglandin synthesis. The prostacyclin thus formed along with NO released by eNOS and nNOS stimulation causes relaxation of smooth muscle cells. Impaired NOS function, rather than NOS expression is considered to be the cause of insufficient NO production and the inability to stimulate the penile corpora cavernosa to elicit a normal erectile response Gonzalez-Cadavid, 2000; Maas, 2003). Prostaglandin E1 and its derivative alprostadil, which induce relaxation mainly through cAMP also enhance erection (Porst, 1996).
Inflammatory processes cause a shift from vasodilatory to vasoconstrictor eicosanoids. Under such conditions NO generated from eNOS and nNOS is not sufficient to cause smooth muscle relaxation.
Oxidative stress contributes to the development of atherosclerosis, endothelial dysfunction, and ED. By reacting with NO itself, or by interfering with NO-mediated pathways, reactive oxygen species (ROS) could contribute to erectile dysfunction. Thus antioxidants will enhance erectile function by scavenging ROS and enhancing bioavailability of NO.
Examples of type V (5) phosphodiesterase inhibitors include, but not limited to, sildenafil, tadalafil, vardenafil, avanafil, Zaprinast®, papaverine and dipyridamole. Other type 5 PDE inhibitors are disclosed in PCT Publication Nos. WO 94/28902, WO 96/16644, U.S. Pat. No. 6,338,862 and U.S. Pat. No. 6,476,037.
Other Potential Applications of PDE5 Inhibitors
Side Effects and Complications of PDE5 Inhibitors
The side effects of PDE inhibitors include hypotension, flushing, headache, nasal congestion and heartburn and these effects are dose dependent (Moreira, 2000). The incidence of cardiovascular events and deaths have been reported with the use of PDE 5 inhibitors (Lim, 2002). This may be due to the fact that PDE5 inhibitors dilate the coronary arteries which makes the patient feel better. This may lead to vigorous physical activity (exercise or intercourse). Such activity may lead to ischemia and heart attack. Also interaction with other drugs including nitroglycerine poses substantial risks. The visual side effects of PDE 5 inhibitors are due to the inhibition of PDE 6 found in the retina. Currently available therapies for ED are palliative, have significant failure rates and side effects, and require treatment prior to each sexual encounter. So novel methods of treatment for patients unresponsive to current treatments are required. In ED, the activity of penile NOS is reduced, or the NO synthesis is not sufficient to produce a normal erectile response. Therefore, stimulation of penile NO synthesis seems to be the ideal treatment for ED. Use of synthetic NO donor compounds have not proved successful due to poor stability and delivery problems of these compounds. Enhancing NO synthesis by administration of the substrate L-arginine is another approach. But the availability of L-arginine is not a rate-limiting step for NOS. Administration of massive doses of L-arginine for long-term is necessary to produce any detectable increase in NO production. This invention describes a practical and efficient method for stimulation of nitric oxide production and enhancing the efficacy of PDE 5 inhibitors in the treatment of ED and other disorders.
Brain mechanisms, particularly activation of dopamine receptors play a major role in normal sexual function (Giuliano, 2001). PDE 5 inhibitors have no effect on brain dopamine activity. Apomorphine and other agents that enhance dopamine also enhance erectile function (Stief, 2003). But these dopaminergic drugs do not enhance penile blood flow. Deprenyl and other MAO inhibitors elevate dopamine levels in the brain and thus can augment sexual function (Knoll, 1989).
Deprenyl and other propargylamine compounds will enhance the efficacy of PDE 5 inhibitors by several mechanisms including stimulation of nitric oxide production and enhanced dopamine activity.
The present invention is based on the discovery that a selective group of compounds, l-deprenyl and propargylamine compounds (monoamine oxidase [MAO] inhibitors), acts synergistically with type 5 phosphodiesterase inhibitors to induce vasodilation and or prevent vasospasm.
Phosphodiesterase type 5 inhibitors potentiate the actions of nitric oxide (NO) by elevating the levels of CGMP, and thus enhance blood flow and erectile function. We have previously shown that l-deprenyl and propargylamine compounds stimulate the production of nitric oxide both in peripheral and cerebral tissues (Thomas, 2001, 1998; U.S. Pat. No. 6,432,991). MAO inhibitors also elevate the levels of dopamine, a key mediator of sexual function in the brain. We show here that MAO inhibitors augment the actions of PDE5 inhibitors, reduce side effects, and enable the reduction of the dose of PDE inhibitors.
The flow chart below illustrates sites of actions of these compounds.
It has been shown that l-deprenyl and other propargylamine derivatives induce, NO production, vasodilation, and endothelial protection (Thomas, 2001, 1998). These compounds will act synergistically with PDE inhibitors. Thus l-deprenyl like compounds may be useful in augmenting the effects of inhibitors of various classes of PDE inhibitors.
The beneficial actions of l-deprenyl and propargylamine compounds may also be mediated by the following actions—nitric oxide production, vasodilation, endothelial protection, smooth muscle relaxation, antioxidant action, free radical scavenging, antiapoptotic action, stimulation of antioxidant enzymes, anti-inflammatory activity, monoamine oxidase inhibition, enhanced dopamine activity, inhibition of phosphodiesterase, enhancement of monoamine activity, neuroprotection, antidepressant, antidiabetic, etc. (Thomas, 2001, 1998;-Maia, 2004). In addition l-deprenyl may enhance sexual function by elevating dopamine levels in the brain through MAO-B inhibition.
The synergestic effect of type 5 PDE inhibitors and l-deprenyl or propargylamine compounds can be utilized in a number of conditions. In one preferred embodiment, combinations of l-deprenyl and one or more PDE5 inhibitors are administered to a male subject to treat erectile dysfunction and other sexual disorders. In another preferred embodiment, combinations of l-deprenyl and PDE5 inhibitors are administered to a female subject to treat sexual dysfunction. In another preferred embodiment, combinations of l-deprenyl and PDE5 inhibitors are administered to a subject to prevent or reduce vasospasm of a coronary artery or bypass graft. In another preferred embodiment, combinations of l-deprenyl and PDE5 inhibitors are administered to produce vasodilation.
In another preferred embodiment, combinations of l-deprenyl and PDE5 inhibitors are administered to a subject to prevent or treat conditions such as:
Monoamine oxidase inhibitors contemplated in the invention include l-deprenyl (selegiline), r-deprenyl, desmethyl selegiline, clorgyline, pargyline, iproniazid, nialamide, phenelzine, tranylcypromine, quinacrine, hydrazine, carboxamide, RO 16-6491, RO 41-1049, propargylamines (eg. Rasagiline, Lazabemide), N-propargylamine compounds, N-methyl propargylamine, and N-methyl-N-(2-pentyl)-propargylamine. Other MAO A and B inhibitors, both natural and synthetic are also contemplated. Chemical modifications, derivatives and metabolites of MAO inhibitors, both natural and synthetic are also contemplated in the invention. Compounds of the invention with one or more asymmetric carbon atoms may exist as enantiomers, diastereomers or as racemic mixtures, it is to be understood that the present invention anticipates and includes within its scope such isomers and mixtures.
Phosphodiesterase inhibitors contemplated in the invention include type 5 phosphodiesterase inhibitors such as, but not limited to, sildenafil, tadalafil, vardenafil, avanafil, zaprinast, dipyridamole, propentofylline, papverine, IBMX, pyrazolopyrimidinones, griseolic acid derivatives, 2-phenylpurinones, phenylpyridone derivatives, pyrimidines, purines, quinazolines, phenylpyrimidinones, imidazoquinoxalinones, phenylpyridones, 4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)propoxy]-3(2H)pyridazinone, 1-[4-[(1,3-benzodiozol-5-9pyridylmethylamino)-6-chloro-2-quinazolinyl]-4-piperidine-carboxylic acid, (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifloromethyl)-phenylmethyl-5-methyl cyclopent-4,5]imidazo[2.1-b]purin-4(3H)one, furazlocillin, cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one, 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate, 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3(2H) pyridazinone, 1-methyl-5-(5morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one, 1-[4[(1,3-benzodioxol-5-methyl)amino]-6-chloro-2-quinazolinyl]4-piperidine carboxylic acid. Salts, derivatives and metabolites of phosphodiesterase 5 inhibitors are also included. Other type 5 PDE inhibitors are disclosed in PCT Publication Nos. WO 94/28902, WO 96/16644, U.S. Pat. No. 6,338,862 and U.S. Pat. No. 6,476,037.
The optimal doses MAO inhibitor in a pharmaceutical composition is in the amounts of 0.1 to 100-mg/kg body weight and the doses of MAO inhibitors in the pharmaceutical composition may be in the amounts of 0.1-50.0 mg/kg. Depending on the application, the optimal doses of PDE5 inhibitors will vary from 0.1 mg to 500 mg. It is also contemplated that compounds of the invention will also enhance the actions of other PDE inhibitors, more specifically type I, II, III, IV, VI, and VII.
It is also contemplated that compounds of the invention will enhance the effects of other modalities of treatment for erectile dysfunction. More specifically these modalities include psychotherapy, surgical methods, implants, and vacuum methods.
Pharmaceutical Formulations and Modes of Administration
According to this invention, one or more of PDE5 inhibitors are administered in conjunction with l-deprenyl or propargylamine compounds to an individual prone to erectile dysfunction and or other conditions listed previously. While this invention is described in terms of application to human subjects, veterinary applications are contemplated within the scope of this invention. The PDE inhibitor and l-deprenyl can be administered simultaneously or sequentially. Both PDE inhibitor and l-deprenyl can be administered by the same modality (in the same preparation) or they can be administered in different formulations and/or by different modalities.
The PDE inhibitors, and or l-deprenyl may be administered in the form of salts, esters, amides, prodrugs, derivatives and may be prepared using standard procedures known to those skilled in the art.
Type 5 PDE inhibitors and l-deprenyl may be administered as parenteral, topical, oral, or local administration such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment of erectile dysfunction and other conditions. The pharmacological compositions can be administered in a variety of unit dosage forms or kits depending upon the method of administration. Suitable unit dosage forms include, but are not limited to powders, tablets, capsules, injectibles, lozenges, creams, suspensions, suppositories, etc. The concentration of active ingredients in the formulation can vary and will be based on the nature and extent of the disease, body weight, or fluid volumes in accordance with the needs of the subject.
The following examples illustrate various actions of MAO inhibitors which enhance the biological actions of phosphodiesterase inhibitors, but do not limit the scope of the invention in any way. Further aspects of the invention, based on the disclosure above and the following examples, will be apparent to the person of ordinary skill in the art.
Rabbits were treated orally with 1 mg/kg of l-deprenyl orally. The relaxation of the isolated corpus cavernosa was measured as described under methods. L-deprenyl treated animal showed significantly enhanced relaxation. Inhibition of l-deprenyl effect by methylene blue (
The phosphodiesterase 5 inhibitor dipyridamole produced minimal dilation of rabbit cavernosa, The effect of dipyridamole was enhanced by l-deprenyl (
Vascular dysfunction in diabetic state increases the risk for erectile dysfunction. Corpora cavernosa smooth muscle were isolated from 8 week diabetic rabbits Diabetes was induced in rabbits using alloxan. These animals showed a decreased vasodilatory response (
Oxidized LDL accelerates atherosclerosis and contributes to the pathology of ED.
Platelet aggregation has a major role in the development of atherosclerosis and thrombosis, contributing to endothelial dysfunction and ED.
Leukocyte rolling and migration is a measure of inflammatory reaction, which is an early event in atherosclerosis and ED. The anti-inflammatory action of estrogen was potentiated by l-deprenyl as shown in
The results of these examples clearly indicate that, under the conditions tested, the monoamine oxidase inhibitor compounds like l-deprenyl produce dilation of corpus cavernosa and also enhance the effect of phosphodiesterase 5 inhibitors. These actions of MAO inhibitors are mediated through increased production of nitric oxide and cGMP. Other actions of MAO inhibitors which contribute to this effect are also described. Therapeutic methods of using MAO inhibitors and phosphodiesterase inhibitors for the treatment of erectile dysfunction, other male sexual disorders, female sexual disorders, and a variety of vascular, cerebral and peripheral disorders are disclosed. The ratio of MAO inhibitors and phosphodiesterase inhibitors used for these applications can be varied depending on the nature and severity of the disorder, and the affected tissue or organ.
Having now fully described the invention, it will be appreciated by those skilled in the art that the same can be performed within a wide range of equivalent parameters, concentrations and conditions without departing from the spirit and scope of the invention and without undue experimentation.
While the invention has been described in detail with respect to particular preferred embodiments, it should be understood that such description is presented by way of illustration and not limitation. Many changes and modifications within the scope of the present invention may be made without departing from the spirit thereof, and the invention includes all such modifications.
All references cited herein, including journal articles or abstracts, published or corresponding U.S. or foreign applications, or any other references are entirely incorporated by reference herein, including all data, tables, figures, and text presented in the cited references. Additionally, the entire contents of the references cited within the references cited herein are also entirely incorporated by references.
Reference to known methods, steps, or conventional methods, is not in any way an admission that any aspect, description or embodiment of the present invention is disclosed, taught or suggested in the relevant art.
The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art (including the contents of the references cited herein), readily modify and/or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance presented herein, in combination with knowledge of one of ordinary skill in the art.
1. Induction of Diabetes
New Zealand white rabbits (body weight 3.0 kg) were injected intravenously with alloxan (via the lateral ear vein) at a standard dose of 65 mg/kg. Urine was monitored over the duration of diabetes for glucose, ketone bodies and proteins.
1. Preparation of Penile Tissue
After 6 months of alloxan treatment, rabbits (together with age matched controls) were killed by cervical dislocation and penises were excised and placed in DMEM pre-gassed with 95% oxygen and 5% carbon dioxide. Epidermal and connective tissue, urethra and corpus spongiosum were carefully excised from the penis. The corpora cavernosa was then cut longitudinally into two equal segments and then transversely into segments (approx. 2 mm×2 mm×10 mm).
2. Organ Chamber Experiments
Strips of corpus cavernosum were studied in 10.0 mL organ chambers for isomtric tension measurement. The strips were tied with a silk thread to a wire connected to a force transducer on one end and fixed with silk ties to a metallic support on the other end. The organ chambers contained physiologic salt solution composed of NaCl2, 118.3 mM; KCl, 4.7 mM; MgSO4, 0.6 mM; KH2PO4, 1.2 mM; CaCl2, 2.5 mM; NaHCO3, 25 mM: calcium EDTA, 0.026 mM and glucose 11.1 mM/. The solution was gassed with 95% oxygen and 5% carbon dioxide. The temperature was maintained at 37° C. To obtain optimal resting isometric tension for contraction, the strips were stepwise stretched for a period of approximately two hours. Resting tension was adjusted to the optimal isometric tension for contraction for each group by determining the tension at which contraction to phenylephrine (1×10−6 M) was maximal. After the initial equilibration in the organ bath, the tissues were optimally stretched and contracted with phenylephrine. Once a steady contraction was obtained, the tissues were relaxed by the addition of the phosphodiesterase inhibitors, Sildenafil and Dipyridamol or l-deprenyl. In some studies the phosphodiesterase inhibitors were added prior to contraction with phenylephrine and then l-deprenyl was added. The results were expressed as percent of phenylephrine induced contraction.
3. Measurement of cGMP
The penile segments in triplicate was placed in 200 μl of DMEM buffer at 37° C. and gassed with 95% air and 5% carbon dioxide and equilibrated for an hour with occasional removal of the buffer (3-4 times) and replacement with fresh buffer. The various drugs were added to the buffer and the incubations were continued for another 10 min. The reactions were stopped by the addition of 200 μL of 1 mol/L perchloric acid and the tissues were sonicated for 60 sec. After centrifugation at 1000×g for 15 minutes, the supernatants were removed and neutralized with 1 mol/L K3PO4. Aliquots were taken and then acetylated with triethylamine/acetic anhydride (1:2, v/v). After appropriate dilution with phosphate buffer, the cGMP concentrations were measured by radioimmunoassay.